title: Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch.
abstract: Cerebrovascular dysfunction is strongly associated with neonatal intracranial hemorrhage (ICH) and stroke in adults. Cerebrovascular endothelial cells (ECs) play important roles in maintaining a stable cerebral circulation in the central nervous system by interacting with pericytes. However, the genetic mechanisms controlling the functions of cerebral ECs are still largely unknown. Here, we report that disruption of Smad4, the central intracellular mediator of transforming growth factor-β (TGF-β) signaling, specifically in the cerebral ECs, results in perinatal ICH and blood-brain barrier breakdown. Furthermore, the mutant vessels exhibit defective mural cell coverage. Smad4 stabilizes cerebrovascular EC-pericyte interactions by regulating the transcription of N-cadherin through associating with the Notch intracellular complex at the RBP-J binding site of the N-cadherin promoter. These findings uncover a distinct role of endothelial Smad4 in maintaining cerebrovascular integrity and suggest important implications for genetic or functional deficiencies in TGF-β/Smad signaling in the pathogenesis of cerebrovascular dysfunction.
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, China.
authors.forename: Fangfei
authors.initials: F
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Lan
authors.forename: Youliang
authors.initials: Y
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Guan
authors.initials: G
authors.lastname: Yang
authors.forename: Fanwei
authors.initials: F
authors.lastname: Meng
authors.forename: Hua
authors.initials: H
authors.lastname: Han
authors.forename: Anming
authors.initials: A
authors.lastname: Meng
authors.forename: Yaping
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology*; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage; D002560:Cerebrovascular Circulation; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D055785:Gene Knockdown Techniques; D051379:Mice; D008822:Mice, Transgenic; D020286:Pericytes / Q000166:cytology / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015820:Cadherins; D051880:Receptors, Notch; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta